My laboratory is involved in studies to genetically modify autologous lymphocytes to improve their anti-tumor activity. In 1990 we reported the first studies of gene transfer in humans which involved the adoptive transfer of TIL transduced with a marker gene encoding neomycin phosphotransferase. These studies suggested the possibility that genes could be inserted into lymphocytes to improve their anti-tumor efficacy. We have now made progress in this area by developing techniques for the high efficiency transduction of human lymphocytes. The genes encoding high affinity anti-tumor T cell receptors (TCR) that recognize antigens on melanomas and common epithelial cancers have been identified and clinical trials to use autologous T cells transduced with these TCRs have been performed. In clinical studies we have shown that up to 30% of patients with metastatic melanoma will achieve objective clinical cancer regressions when treated with their autologous lymphocytes that have been transduced with T cell receptors that recognized the MART-1 or gp100 melanoma antigens. These were the first studies showing that TCR transduced lymphocytes could mediate cancer regression. T cell receptors have now been identified that recognize NY-ESO-1 and MAGE-A3 epitopes that have also been used to mediate cancer regression in patients. Using cells transduced with a TCR reactive with the NY-ESO-1 cancer testes antigen 10 of 19 melanoma patients and 10 of 15 synovial cell sarcoma patients have had objective responses. Chimeric antigen receptors have been developed that recognize CD19 cell surface antigens on B cell malignancies and the EGFRvIII mutation expressed on glioblastomas. Clinical trials are being performed to study the treatment of patients with a variety of cancer types using these transduced cells. Multiple patients treated with cells transduced with a chimeric receptor targeting CD19 have had substantial responses. Up to 80% of patients treated have had objective responses in the absence of IL-2 administration.